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Therapeutic applications of antigens or epitopes associated with impaired cellular peptide processing, e.g. expressed on rma-s cells transfected with a b7-1 gene

a technology of cellular peptide and antigen, which is applied in the field of therapeutic applications of antigens or epitopes associated with impaired cellular peptide processing, can solve the problems of escape variants, life-threatening meningitis, and the loss of antigen processing mechanisms of tumours

Inactive Publication Date: 2003-05-08
ACCURO IMMUNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0081] Immunization with syngenic TAP-deficient cells can protect against tumour growth in vivo of both TAP-deficient and TAP-expressing tumour cells (Examples 5, 9).

Problems solved by technology

One problem is that different tumours contain different proteins, and that MHC molecules and thereby the peptides that attach to the MHC molecules, vary between individuals, as well as between tumours.
Another problem is that many tumours have lost parts of the antigen processing mechanism, e.g. TAP, and, therefore, they are not discovered by conventional T cells.
Furthermore, the development and application of immunotherapy protocols today will be confronted with the problem of escape variants (with e.g. TAP-defects), which might even be selected by the treatment given.
Most persons with symptoms have oral ulcers, which may be very disturbing though they do not affect life-span.
An uncommon severe complication is a meningitis which may be life-threatening.
HSV can also cause vaginal ulcers which can cause a life-threatening infection in newborn children of infected mothers.

Method used

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  • Therapeutic applications of antigens or epitopes associated with impaired cellular peptide processing, e.g. expressed on rma-s cells transfected with a b7-1 gene
  • Therapeutic applications of antigens or epitopes associated with impaired cellular peptide processing, e.g. expressed on rma-s cells transfected with a b7-1 gene
  • Therapeutic applications of antigens or epitopes associated with impaired cellular peptide processing, e.g. expressed on rma-s cells transfected with a b7-1 gene

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0103] RMA-S Cells transfected with B7-1 (CD80) elicit CTL that recognize non-transfected RMA-S cells.

[0104] B6 mice were immunized with three weekly s.c. injections of 10.sup.7 irradiated (100 Gray (Gy)) tumour cells. Tumours used were serially passaged as ascites cell lines in 4 Gy irradiated mice. The tumour cells were TAP-2 deficient ones, called RMA-S cells (derived from the Rauscher leukaemia virus-induced mouse T-cell lymphoma RBL-5 of B6 origin (44)), which were transfected with B7-1, i.e. 2.times.10.sup.6 RMA-S cells were incubated with 10 .mu.l LIPOFECTAMINE (Life Technologies Gaithersburg, Md.) and 1 .mu.g of the murine B7-1 gene cloned in a pSRIneo plasmid (45), a gift from Bristol Meyers Inc, Seattle, to Prof Klas Krre. Transfected cells were selected on GENETICIN (Life Technologies, Gaithersburg, Md.) at a concentration of 1 mg / ml. The 1% most positive fraction of the B7-1 expressing RMA-S cells were sorted on a FACS VANTAGE cell sorter (Becton Dickinson, Mountain View...

example 2

[0108] CTL recognition requires the presence of MHC class I molecules and the absence of TAP in the target cell.

[0109] A TAP-2 transfectant of RMA-S (RMA-S.TAP2 cells, also referred to as RMA-S II 5.9 cells, were derived by transfection of RMA-S with the murine TAP-2 gene (46)) was virtually resistant to lysis by RMA-S.B7-1 elicited CTL (FIG. 2A) as in Example 1. This indicated that the epitopes were recognized preferentially in cells devoid of TAP expression. In line with this, Con A blasts from TAP1 - / - mice were highly sensitive to lysis, whereas Con A blasts from B6 mice were resistant to lysis. Con A blasts from TAP1 / .beta..sub.2m - / - (double mutant) mice were resistant to lysis, suggesting an MHC class I dependence in the CTL recognition of epitopes (FIG. 2B).

[0110] Indeed, the human TAP-deficient cell line T2 transfected with H-2K.sup.b was sensitive to lysis by RMA-S.B7-1 elicited CTL, while non-transfected T2 cells were resistant (FIG. 2C). Taken together, these results ind...

example 3

[0111] TAP1 - / - splenocytes elicit CTL that recognize TAP1 - / - Con A blasts and RMA-S tumour cells.

[0112] As shown above, CTL elicited by RMA-S.B7-1 killed TAP1 - / - Con A blasts. Accordingly, immunization of B6 mice with splenocytes from TAP1 - / - mice yielded cytotoxic cells that efficiently lysed TAP1 - / - Con A blasts and RMA-S tumour cells while B6 Con A blasts and RMA-S.TAP2 were killed at markedly reduced levels (FIG. 3; data not shown). The killing of the TAP-deficient cells was also seen with effectors from mice depleted of NK (natural killer) cells (data not shown). B6 mice were immunized with two weekly s.c. injections of 50.times.10.sup.6 irradiated (20 Gy) spleen cells.

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Abstract

The following observation shows that antigens or epitopes associated with impaired cellular peptide processing, especially MHC class I dependent, especially antigens associated with impaired TAP-function, can be used for immunization against cancer or as a virus vaccine.

Description

[0001] The present invention relates to use of substances that can induce expression of antigens or epitopes associated with impaired cellular peptide processing, especially MHC class I dependent, for preparation of pharmaceuticals, pharmaceutical compositions or vaccines, that stimulate specific T cell mediated immune responses against cancer and virus infected cells. It also relates to use of antigens or epitopes associated with impaired cellular peptide processing, especially MHC class I dependent, or part thereof, for the same purpose. It also relates to mammalian cells that have been manipulated to express antigens or epitopes associated with impaired cellular peptide processing, especially MHC class I dependent, and to lymphoid cells activated against such MHC class I dependent structures for the same purpose. Furthermore, processes for such manipulation of mammalian cells and for treating human beings as well as kits for use in such manipulations are covered. The present inve...

Claims

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Application Information

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IPC IPC(8): C12Q1/02A61K38/00A61K38/06A61K38/16A61K39/00A61K39/39A61K45/00A61K48/00A61P31/12A61P35/00C12N5/10
CPCA61K38/06A61K38/162A61K39/0011A61K39/39A61K2039/57A61K2039/53A61K2039/55516A61K2039/55522A61K48/00A61P31/12A61P35/00A61K2239/31A61K39/4622A61K2239/38A61K39/461A61K2239/48A61K39/4615A61K39/464402
Inventor WOLPERT, ELISABETHKARRE, KLASPETTERSSON, MAXSANDBERG, JOHAN
Owner ACCURO IMMUNOLOGY
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